Genomic organization and transcriptional units at the myotonic dystrophy locus

Shaw, Duncan; McCurrach, Mila E.; Rundle, S.A.; Harley, H G; Crow, S; Sohn, Robert L.; Thirion, Jean‐Paul; Hamshere, Marion; Buckler, Alan; Harper, Peter S.; Housman, David E.; Brook, David

doi:10.1016/s0888-7543(05)80372-6

Cited by 70 publications

(31 citation statements)

References 21 publications

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“…First, regions of heterochromatin can modulate transcription over a large region, and it is possible that altered expression of genes near the myotonin gene could contribute to the myotonic dystrophy phenotype (21). Second, some genes are preferentially transcribed in regions of heterochromatin, and the loss of the hypersensitive site could theoretically upregulate the transcription of the myotonin gene or an adjacent gene.…”

Section: Resultsmentioning

confidence: 99%

Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.

Otten

Tapscott²

1995

Proc. Natl. Acad. Sci. U.S.A.

174

107

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Myotonic dystrophy is caused by an expansion of a CTG triplet repeat sequence in the 3' noncoding region of a protein kinase gene, yet the mechanism by which the triplet repeat expansion causes disease remains unknown. This report demonstrates that a DNase I hypersensitive site is positioned 3' of the triplet repeat in the wild-type allele in both fibroblasts and skeletal muscle cells. In three unrelated individuals with myotonic dystrophy that have large expansions of the triplet repeat, the allele with the triplet repeat expansion exhibited both overall DNase I resistance and inaccessibility of nucleases to the adjacent hypersensitive site. These results indicate that the triplet repeat expansion alters the adjacent chromatin structure, establishing a region of condensed chromatin, and suggests a molecular mechanism for myotonic dystrophy.

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Section: Resultsmentioning

confidence: 99%

Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.

Otten

Tapscott²

1995

Proc. Natl. Acad. Sci. U.S.A.

174

107

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“…In view of these findings, we have performed a series of experiments to compare the distribution of expanded and wild-type DMPK alleles in RNA from nuclear and cytoplasmic fractions of DM cells. We have also examined the expression of genes 59 (10,17) and DMAHP (12), which f lank DMPK, to establish whether this is affected by repeat expansion.…”

mentioning

confidence: 99%

Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes

Alwazzan

et al. 1997

Proc. Natl. Acad. Sci. U.S.A.

Self Cite

133

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Myotonic dystrophy (DM) is caused by the expansion of a trinucleotide repeat, CTG, in the 3 untranslated region of a protein kinase gene, DMPK. We set out to determine what effect this expanded repeat has on RNA processing. The subcellular fractionation of RNA and the separate analysis of DMPK transcripts from each allele reveals that transcripts from expanded DMPK alleles are retained within the nucleus and are absent from the cytoplasm of DM cell lines. The nuclear retention of DMPK transcripts occurs above a critical threshold between 80 and 400 CTGs. Further analysis of the nuclear RNA reveals an apparent reduction in the proportion of expansion-derived DMPK transcripts after poly(A) ؉ selection. Quantitative analysis of RNA also indicates that although the level of cytoplasmic DMPK transcript is altered in DM patients, the levels of transcripts from 59 and DMAHP, two genes that immediately f lank DMPK, are unaffected in DM cell lines.Myotonic dystrophy (DM) is the most common form of muscular dystrophy affecting adults. It is dominantly inherited and involves many systems, including endocrine, heart, and brain, though principally it is a disease of muscle characterized by myotonia with muscle weakness and wasting (1). DM is associated with the expansion of a CTG repeat located in the 3Ј untranslated region (UTR) of a protein kinase gene, DMPK (2-4) (See Fig. 1). It is not known how this mutation, in a noncoding part of the gene, exerts an effect at the cellular level, and conf licting data have been published about the effect of repeat expansion on DMPK RNA levels in DM tissues and cell lines (5-8). Three models have been proposed to explain the molecular mechanism of DM (9). First, the mutation may directly effect the level of DMPK protein. Second, the mutation may affect the higherorder structure of DNA around the repeat, altering the level of expression of neighboring genes in a field effect (10 -13). Third, the repeat expansion may produce a gain-of-function mutation at either the DNA or RNA level. Recently, foci of DMPK transcripts containing expanded repeats have been reported in the nuclei of DM muscle specimens and fibroblast cell lines (14), and other studies have suggested that a disruption of RNA processing may be critical for the development of DM (15,16). In view of these findings, we have performed a series of experiments to compare the distribution of expanded and wild-type DMPK alleles in RNA from nuclear and cytoplasmic fractions of DM cells. We have also examined the expression of genes 59 (10, 17) and DMAHP (12), which f lank DMPK, to establish whether this is affected by repeat expansion.

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“…The molecular basis of DM1, which is inherited in an autosomal dominant fashion, was identified at the beginning of the 1990s and the genetic defect is localized in chromosome 19 as a trinucleotide CTG expansion (Davies et al, 1983;Brook et al, 1992;Buxton et al, 1992;Fu et al, 1992;Mahadevan et al, 1992;Shaw et al, 1993). The amplified CTG repeat was identified in a protein kinase gene, named DMPK (myotonic dystrophy protein kinase).…”

Section: Myotonic Dystrophymentioning

confidence: 99%

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

Mastroyiannopoulos

Shammas

Phylactou

2010

Biology of the Cell

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Cyprus DM1 (myotonic dystrophy type I) is a common form of muscular dystrophy that affects mainly adults. It is a disease that belongs to the group of defective RNA export diseases, since a major part of the pathogenic mechanism of the disease is the retention of the mutant transcripts in the cell nucleus. The presence of an expanded CUG trinucleotide repeat in the 3 -UTR (3 -untranslated region) of the DMPK (myotonic dystrophy protein kinase) gene causes the attraction of RNA-binding proteins by the nuclear-located mutant transcripts. As a result of the occupation of the RNA-binding proteins, there is defective mis-splicing of several cellular transcripts. This is believed to be a major pathogenic mechanism of the disease and any attempt to repair the activities of the RNA-binding proteins or target the mutant transcripts should be beneficial for the patients. Certain approaches have been described in the literature and they demonstrate progress in various directions. The purpose of the present review is to summarize the successful attempts to tackle the pathogenesis caused by nuclear retention of mutant transcripts in myotonic dystrophy and to discuss the possible gains from such approaches.

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Genomic organization and transcriptional units at the myotonic dystrophy locus

Cited by 70 publications

References 21 publications

Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.

Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure.

Transcriptional abnormality in myotonic dystrophy affects DMPK but not neighboring genes

Tackling the pathogenesis of RNA nuclear retention in myotonic dystrophy

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